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Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks.

Tarczyluk MA, Nagel DA, Rhein Parri H, Tse EH, Brown JE, Coleman MD, Hill EJ - J. Cereb. Blood Flow Metab. (2015)

Bottom Line: In addition, a significant increase in the glycogen content of cells was also observed.The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism.Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic and Clinical Neuroscience, James Black Centre, Institute of Psychiatry, London, UK.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (Aβ1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD(+)/NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism.

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Related in: MedlinePlus

NAD+/NADH ratio, and ATP levels inside the cells after treatment of NT2.N/A with 2 μmol/L amyloid beta (Aβ). (A) NAD+, NADH, and (B) ATP were measured after 6, 24, 48, 72, and 96 hours. Results are expressed as ratio±s.e.m. (A) and nmol/mg protein±s.e.m. (B), n=3. P<0.05 (*), P<0.01 (**), P<0.001 (***). Comparisons between treatments were performed using Students T-test.
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fig6: NAD+/NADH ratio, and ATP levels inside the cells after treatment of NT2.N/A with 2 μmol/L amyloid beta (Aβ). (A) NAD+, NADH, and (B) ATP were measured after 6, 24, 48, 72, and 96 hours. Results are expressed as ratio±s.e.m. (A) and nmol/mg protein±s.e.m. (B), n=3. P<0.05 (*), P<0.01 (**), P<0.001 (***). Comparisons between treatments were performed using Students T-test.

Mentions: NAD+/NADH ratios and ATP levels were measured in NT2.N/A cocultures after treatment with 2 μmol/L Aβ. The NAD+/NADH ratio increased at 24 hours and was followed by a steady decrease at 48, 72, and 96 hours (Figure 6A). Both Aβ treated and control cells followed this trend. There was an initial increase in NAD+/NADH ratio after the treatment with Aβ at 24 hours (control: 0.66±0.06; 2 μmol/L: 0.91±0.02, P<0.05). However, after this time point the ratio was much lower after the Aβ treatment and became significantly lower at 96 hours (control: 0.52±0.03; 2 μmol/L: 0.18±0.01, P<0.001). At 96 hours NAD+ levels in control were 820±17.5 pmol/mg of protein, while after treatment with 2 μmol/L, Aβ levels decreased to 348±20.2 pmol/mg of protein. ATP levels after treatment with 2 μmol/L Aβ decreased from 6 hours, becoming significant at 24 hours (Figure 6B). ATP levels reached their lowest levels at 72 and 96 hours (control: 8.34±0.86 nmol/mg protein; 2 μmol/L: 3.29±0.20 nmol/mg protein, P<0.01).


Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks.

Tarczyluk MA, Nagel DA, Rhein Parri H, Tse EH, Brown JE, Coleman MD, Hill EJ - J. Cereb. Blood Flow Metab. (2015)

NAD+/NADH ratio, and ATP levels inside the cells after treatment of NT2.N/A with 2 μmol/L amyloid beta (Aβ). (A) NAD+, NADH, and (B) ATP were measured after 6, 24, 48, 72, and 96 hours. Results are expressed as ratio±s.e.m. (A) and nmol/mg protein±s.e.m. (B), n=3. P<0.05 (*), P<0.01 (**), P<0.001 (***). Comparisons between treatments were performed using Students T-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528011&req=5

fig6: NAD+/NADH ratio, and ATP levels inside the cells after treatment of NT2.N/A with 2 μmol/L amyloid beta (Aβ). (A) NAD+, NADH, and (B) ATP were measured after 6, 24, 48, 72, and 96 hours. Results are expressed as ratio±s.e.m. (A) and nmol/mg protein±s.e.m. (B), n=3. P<0.05 (*), P<0.01 (**), P<0.001 (***). Comparisons between treatments were performed using Students T-test.
Mentions: NAD+/NADH ratios and ATP levels were measured in NT2.N/A cocultures after treatment with 2 μmol/L Aβ. The NAD+/NADH ratio increased at 24 hours and was followed by a steady decrease at 48, 72, and 96 hours (Figure 6A). Both Aβ treated and control cells followed this trend. There was an initial increase in NAD+/NADH ratio after the treatment with Aβ at 24 hours (control: 0.66±0.06; 2 μmol/L: 0.91±0.02, P<0.05). However, after this time point the ratio was much lower after the Aβ treatment and became significantly lower at 96 hours (control: 0.52±0.03; 2 μmol/L: 0.18±0.01, P<0.001). At 96 hours NAD+ levels in control were 820±17.5 pmol/mg of protein, while after treatment with 2 μmol/L, Aβ levels decreased to 348±20.2 pmol/mg of protein. ATP levels after treatment with 2 μmol/L Aβ decreased from 6 hours, becoming significant at 24 hours (Figure 6B). ATP levels reached their lowest levels at 72 and 96 hours (control: 8.34±0.86 nmol/mg protein; 2 μmol/L: 3.29±0.20 nmol/mg protein, P<0.01).

Bottom Line: In addition, a significant increase in the glycogen content of cells was also observed.The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism.Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic and Clinical Neuroscience, James Black Centre, Institute of Psychiatry, London, UK.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (Aβ1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD(+)/NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism.

Show MeSH
Related in: MedlinePlus